The high energy demands of the postnatal mammalian heart are met primarily by ATP produced by oxidation of fatty acids in the numerous mitochondria of the differentiated cardiac myocyte. The importance of this specialized high capacity energy production system for the normal function of the adult heart is evidenced by the development of cardiomyopathy and heart failure in humans with inherited and acquired abnormalities in mitochondrial function. With aging, the heart reverts to the fetal preference for glucose oxidation over mitochondrial fatty acid oxidation, coincident with an overall decline in mitochondrial oxidative function. The contribution of these changes to the development and progression of age-related cardiovascular diseases is unknown. The recent identification of the inducible transcriptional coactivator PGC-1alpha has provided important insight into the gene regulatory mechanisms responsible for maintenance of cardiac mitochondrial oxidative capacity. Expression of PGC-1alpha is induced in heart following birth and with exercise and short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1alpha in cardiac myocytes in culture or in the hearts of transgenic mice increases mitochondrial number and stimulates respiration. Recent exciting data in rodents implicates PGC-1alpha in the known beneficial effect of caloric restriction on aging. This proposal seeks to define the role for PGC-1alpha as a critical regulatory molecule in the control of cardiac mitochondrial number and function in the developing and aging heart using loss-of-function and conditional gain-of-function strategies in genetically modified mice. Emphasis will be given to postnatal development and aging - developmental periods with significant changes in cardiac mitochondrial energy metabolism and mechanical function. The use of caloric restriction in aged mice will further assess the primary role of PGC-1alpha in promoting and maintaining the heart's abundant mitochondrial oxidative capacity and will define its link to cardiac aging.